There is now convincing evidence that the calcium ion can play a critical role in cell killing in the central nervous system and other tissues. Recent research has established some of the biochemical mechanisms by which intracellular Ca2+ overload can trigger either necrotic or apoptotic cell death, and a number of studies have shown that prevention of Ca2+ overload by pretreatment with either Ca2+ chelators, receptor antagonists or channel blockers can rescue cells that would otherwise die. Similarly, cells which express high levels of certain Ca(2+)-binding proteins (e.g. calbindin-D28K) seem to be more resistant to killing. Thus, it appears that the development of improved strategies to prevent Ca2+ overload will be of importance for neuroprotection. The role of the calcium ion as intracellular regulator of many physiological processes is now well established. Thus, the effects of a variety of hormones and growth factors have been found to be mediated by transient increases in the level of cytosolic Ca2+, which frequently assume oscillatory patterns (see Carafoli, 1989 and Berridge, 1991 for reviews). Most often, the Ca2+ increase is initiated by the release of Ca2+ from intracellular stores followed by the stimulation of influx of extracellular Ca2+. Most regulatory effects of Ca2+ are mediated by Ca(2+)-binding proteins (e.g. calmodulin) and achieved by alterations of the phosphorylation state of target proteins. Along with this knowledge has come the understanding that Ca2+ can also play a determinant role in a variety of pathological and toxicological processes. It has long been recognized that Ca2+ accumulates in necrotic tissue, and more recent work has revealed that a disruption of intracellular Ca2+ homeostasis is frequently associated with the early development of cell injury (Schanne et al., 1979; Jewell et al., 1982; Fleckenstein et al., 1983). This led to the formulation of the calcium hypothesis of cell injury, proposing that perturbation of intracellular Ca2+ homeostasis may be a common step in the development of cytotoxicity. Support for this hypothesis has come from a large number of studies demonstrating that the calcium ion plays a critical role in cytotoxicity and cell killing in many tissues, notably the central nervous system and the immune system (see Nicotera et al., 1992 for review).